Plant-Derived Enzyme is Potential Source for Enzyme Replacement Therapy

An enzyme structurally similar to alpha-galactosidase A (GLA), present in a close relative of the tobacco plant, was able to rescue Fabry disease patients’ cells.

These findings suggest that plant alpha-galactosidases can be a potential new source for enzyme replacement therapy in Fabry disease.

The study “Nicotiana benthamiana α-galactosidase A1.1 can functionally complement human α-galactosidase A deficiency associated with Fabry disease” was published in the Journal of Biological Chemistry.

Fabry disease is an inherited disorder that arises from mutations in the GLA gene, which encodes for an enzyme called alpha-galactosidase A.

The enzyme is active in small recycling structures inside the cells – called lysosomes – where it breaks down fatty substances. The mutated form of alpha-galactosidase A, however, impairs its function, preventing it from breaking down the fat effectively and leading it to accumulate inside cells.

Enzyme replacement therapy (ERT) with two therapeutic enzymes, commercialised as Replagal (agalsidase alfa) and Fabrazyme (agalsidase beta), is currently used as a therapeutic strategy. ERT provides an external source of alpha-galactosidase A, where the enzyme is produced in mammalian cells.

However, the effectiveness of present ERT interventions is considered to be poor: ERTs can fail to reach all organs, particularly the heart and kidney, which often develop complications in Fabry patients. According to researchers, this possibly occurs due to the use of insufficient therapeutic enzyme to penetrate these organs. The high costs involved in the production of human alpha-galactosidase A preparations hamper  the use of higher concentrations of the therapy.

Importantly, patients often react to ERTs by producing antibodies against alpha-galactosidase A, decreasing its effectiveness.

Dutch researchers have now investigated whether an alpha-galactosidase they called  A1.1, found in the Nicotiana benthamiana plant, could help degrade the fat that accumaltes inside the cells of Fabry disease patients.

After isolating the plant enzyme, the team saw that its structure revealed marked similarities with the human alpha-galactosidase A. Moreover, A1.1 was able to break down both types of fat that accumulate in Fabry’s disease – globotriaosylceramide and globotriaosylsphingosine – with an efficiency similar to that of Fabrazyme (agalsidase beta).

Researchers then tested A1.1’s effectiveness in a specific type of cells, called fibroblasts, from Fabry disease patients. Cells incubated overnight with A1.1 had lower levels of fat accumulation, reaching those commonly found in healthy fibroblasts.

Production of a plant-derived alpha-galactosidase A enzyme carries considerable lower costs compared to those of current human recombinant enzymes, allowing the use of higher doses. Also, A1.1 showed no cross-reactivity with neutralizing antibodies directed against the human form of the enzyme.

Overall, these results support “further research on the optimization of plant alpha-galactosidases such as A1.1 to reduce toxic lysoGb3 [globotriaosylsphingosine] in Fabry disease should be considered in order to meet the need for an affordable treatment of this devastating disorder,” researchers wrote.